Endometrial Intraepithelial Neoplasia Clinical Correlates and Outcomes

Objective To estimate cancer outcome and outcome predictors of women with endometrial intraepithelial neoplasia (EIN). Methods Outcomes of women with first diagnosis of EIN (“index biopsy”) was determined by follow-up pathology. Patient characteristics were correlated with EIN regression, EIN persistence, and progression to cancer. Results Fifteen percent (9.8-20.8%, 26/177) of index EIN biopsies had concurrent cancer. Of the women with cancer-free index EIN biopsies, and follow-up by hysterectomy or more than 18 months surveillance, 25% (18.4-33.3%, 36/142) showed regression, 35% (27.4-43.7%, 50/142) persistence, and 39% (31.3-48.0%, 56/142) progression. Non-white ethnicity and progestin treatment reduced cancer outcomes (OR 0.16 (0.03,0.84) and 0.24 (0.08, 0.70) respectively), while body mass index (BMI) greater than 25 increased malignant outcomes (BMI 25 or higher, OR 3.05 (1.10,8.45)). Conclusion EIN confers a high risk of cancer, but individual patient outcomes cannot be predicted. Management should include exclusion of concurrent carcinoma and consideration of hysterectomy

Identifying the molecular signature of the interstitial deletion 7q subgroup of uterine leiomyomata using a paired analysis.

Uterine leiomyomata (UL), the most common neoplasm in reproductive-age women, have recurrent cytogenetic abnormalities including del(7)(q22q32). To develop a molecular signature, matched del(7q) and non-del(7q) tumors identified by FISH or karyotyping from 11 women were profiled with expression arrays. Our analysis using paired t-tests demonstrates this matched design is critical to eliminate confounding effects of genotype and environment that underlie patient variation. A gene list ordered by genome-wide significance showed enrichment for the 7q22 target region. Modification of the gene list by weighting each sample for percent of del(7q) cells to account for the mosaic nature of these tumors further enhanced the frequency of 7q22 genes. Pathway analysis revealed two of the 19 significant functional networks were associated with development and the most represented pathway was protein ubiquitination, which can influence tumor development by stabilizing oncoproteins and destabilizing tumor suppressor proteins. Array CGH (aCGH) studies determined the only consistent genomic imbalance was deletion of 9.5 megabases from 7q22-7q31.1. Combining the aCGH data with the del(7q) UL mosacism-weighted expression analysis resulted in a list of genes that are commonly deleted and whose copy number is correlated with significantly decreased expression. These genes include the proliferation inhibitor HPB1, the loss of expression of which has been associated with invasive breast cancer, as well as the mitosis integrity-maintenance tumor suppressor RINT1. This study provides a molecular signature of the del(7q) UL subgroup and will serve as a platform for future studies of tumor pathogenesis